Introduction: We have previously shown that IGFBP-6 inhibits angiogenesis as well as proliferation and survival of rhabdomyosarcoma cells. However, it promotes migration, and binding to prohibitin-2 is involved in this IGF-independent action. The IGF system is implicated in ovarian cancer, so we studied the effects of IGFBP-6 in ovarian cancer cells.
Methods: We defined the effects of IGFBP-6 (both wild type (wt) and a non-IGF-binding mutant (m)) on migration of HEY and SKOV-3 ovarian cancer cells, which respectively represent aggressive and transitional cancers, using a microchemotaxis chamber. Erk and Jnk phosphorylation were measured by Western blotting.
Results:IGF-II, wt- and mIGFBP-6 each promoted SKOV3 cell migration by 77-98% (p<0.005). In contrast, IGF-II increased HEY cell migration to 155 ± 29% of control (p<0.001), while wtIGFBP-6 and mIGFBP-6 decreased migration to 62 ± 5% and 66 ± 3% respectively (p<0.001). In these cells, coincubation with IGF-II significantly increased migration in the presence of wt but not mIGFBP-6.
We have previously shown that MAP kinase pathways are involved in IGFBP-6-induced rhabdomyosarcoma cell migration, so we compared activation of these pathways in HEY and SKOV3 cells.Wt and mIGFBP-6 increased Erk phosphorylation by 62-100% in both cell lines (p<0.05). WtIGFBP-6 also increased Jnk phosphorylation by 138-153% in both cell lines (p<0.05), but the effect of mIGFBP-6 was less clear. Erk and Jnk pathways inhibitors partially reversed IGFBP-6-induced effects on migration.
Conclusions: IGFBP-6 has opposing effects on migration of HEY and SKOV3 ovarian cancer cells, but activates MAP kinase pathways in both. Delineating the pathways underlying the differential effects on migration will increase our understanding of ovarian cancer metastasis and shed new light on the IGF-independent effects of IGFBP-6, which may in turn lead to the development of an optimized IGFBP-6-based therapeutic that is antitumorigenic and not promigratory.